PUBLICATION
Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: Further delineation of a new chaperone-mediated tubulinopathy
- Authors
- Pode-Shakked, B., Barash, H., Ziv, L., Gripp, K.W., Flex, E., Barel, O., Carvalho, K.S., Scavina, M., Chillemi, G., Niceta, M., Eyal, E., Kol, N., Ben-Zeev, B., Bar-Yosef, O., Marek-Yagel, D., Bertini, E., Duker, A.L., Anikster, Y., Tartaglia, M., Raas-Rothschild, A.
- ID
- ZDB-PUB-161105-25
- Date
- 2017
- Source
- Clinical genetics 91(5): 725-738 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Child, Preschool
- Developmental Disabilities/genetics*
- Embryo, Nonmammalian
- Epilepsy/genetics
- Female
- Humans
- Infant
- Intellectual Disability/genetics
- Magnetic Resonance Imaging
- Male
- Microcephaly/genetics*
- Microtubule-Associated Proteins/chemistry*
- Microtubule-Associated Proteins/genetics*
- Microtubule-Associated Proteins/metabolism
- Microtubules/genetics
- Microtubules/pathology
- Seizures/diagnostic imaging
- Seizures/genetics*
- Zebrafish/embryology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 27807845 Full text @ Clin. Genet.
Citation
Pode-Shakked, B., Barash, H., Ziv, L., Gripp, K.W., Flex, E., Barel, O., Carvalho, K.S., Scavina, M., Chillemi, G., Niceta, M., Eyal, E., Kol, N., Ben-Zeev, B., Bar-Yosef, O., Marek-Yagel, D., Bertini, E., Duker, A.L., Anikster, Y., Tartaglia, M., Raas-Rothschild, A. (2017) Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: Further delineation of a new chaperone-mediated tubulinopathy. Clinical genetics. 91(5):725-738.
Abstract
Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly-described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping